Hypercholesterolemia is known to be one of the prime risk factors for ischemic cardiovascular disease, such as arteriosclerosis. Bile acid sequestrants have been used to treat this condition; they seem to be moderately effective but they must be consumed in large quantities, i.e., several grams at a time, and they are not very palatable.
MEVACOR.RTM. (lovastatin) and ZOCOR.RTM. (simvastatin), now commercially available, are members of a group of very active antihypercholesterolemic agents that function by limiting cholesterol biosynthesis by inhibiting the enzyme HMG-CoA reductase.
Squalene synthase is the enzyme involved in the first committed step of the de novo cholesterol biosynthetic pathway. This enzyme catalyzes the reductive dimerization of two molecules of farnesyl pyrophosphate to form squalene. The inhibition of this committed step to cholesterol should leave unhindered biosynthetic pathways to ubiquinone, dolichol, and isopentyl t-RNA.
Previous efforts at inhibiting squalene synthase have employed pyrophosphate or pyrophosphate analog-containing compounds such as those described in P. Ortiz de Montellano et al. J. Med. Chem. 20, 243 (1977) and E.J. Corey and R. Volante, J. Am. Chem. Soc.,98, 1291 (1976). S. Biller (U.S. Pat. No. 4,871,721) describes isoprenoid (phosphinylmethyl) phosphonates as inhibitors of squalene synthase.
Recently, certain nonphosphorus containing inhibitors of squalene synthase have been isolated as natural products. The natural product inhibitor known as Zaragozic Acid A and its use as a cholesterol lowering agent and antifungal agent is described in U.S. Pat. Nos. 5,096,923 issued Mar. 17, 1992, and 5,053,425 issued Oct. 1, 1991. These patents disclose preparation of Zaragozic Acid A by an aerobic fermentation procedure employing a fungal culture MF 5453 (ATCC 20986). MF 5453 is an unidentified sterile fungus isolated from a water sample obtained from the Jalon river in Zaragoza, Spain. A need still remains for a more effective squalene synthase inhibitor, i.e., one that provides a greater antihypercholesterlemic effect and exhibits a good safety profile.
The present invention is directed to photochemical reaction products of Zaragozic Acid A.